Human Aging: (1) Human brain blood flow and glucose metabolism have been considered to decline with age, suggesting reduced brain functional activity. However, we showed that brain glucose metabolism, measured by positron emission tomography (PET) in the "resting state" and corrected for brain atrophy, did not decline significantly with age in healthy men and women. (2) In vivo brain imaging suggests that cognitive processing and attention can stimulate the brain and consolidate synaptic connections during early development. This consolidation can increase brain adaptive changes to a stressful environment, and in some cases promote evolution of more cognitively capable primates. Added to this can be the greater memory and contribution of older subjects to kinships. Alzheimer disease (AD): (1) The patients with Alzheimer's disease had significantly lower glucose metabolism than healthy comparison subjects in parietal, temporal, occipital, frontal, and posterior cingulate cortices. One year later, the patients with Alzheimer's disease had significant declines in glucose metabolism in parietal, temporal, frontal, and posterior cingulate cortices. These findings support the feasibility of using PET as an outcome measure to test the ability of treatments to attenuate the progression of Alzheimer's disease. (2) A multicenter longitudinal study was conducted on 284 suspected AD patients who underwent PET and cognitive testing. In neuropathologically confirmed AD cases, PET patterns identified patients with AD with a sensitivity of 94% and a specificity of 73%. The initial PET scan predicted subsequent disease with a probability of < 0.05. Thus, PET can be used for the early diagnosis of patients with AD or neurodegenerative disease generally, with a negative scan making the likelihood of disease unlikely. (3) Activation in which stimulus intensity is varied parametrically can be used to evaluate synaptic integrity in AD patients by means of PET or functional magnetic resonance imaging (fMRI). Brain activation in mildly-demented AD patients presented with a delayed match-to-sample visual stimulus test demonstrated a significantly different pattern from the pattern in control subjects, thus distinguishing the two groups. The abnormal AD pattern in the AD patients was associated with reduced accuracy as response delay was increased from 1 to 16 seconds, whereas accuracy was unchanged in the controls within increasing delay. The abnormal AD PET pattern suggested functional disconnection between prefrontal cortex and hippocampus. (4) In a PET study of patients with a visual variant of AD, having Balint's syndrome, brain glucose metabolism was reduced in visual areas before and after atrophy correction, compared with healthy aging where metabolism corrected for atrophy does not decline. (5) The volume of the anterior corpus callosum, measured with magnetic resonance imaging (MRI), was shown to be a surrogate marker of brain metabolic dysfunction in AD. In AD patients, its volume was reduced in proportion to reduced glucose metabolism, measured with PET, in frontal and parietal cortical brain regions. (6) In AD patients, 1H-magnetic resonance spectroscopy (MRS) with external standards demonstrated a reduced brain concentration of N-acetylaspartic acid but increased concentrations of myoinositol and creatine. As the latter increases were statistically significant in mildly demented AD patients, 1H-MRS can be used to diagnose early AD. (7) In the predementia phase of Down's syndrome, significant volume changes in medial temporal lobe structures occur with age and are related to memory. These structures are affected early in Alzheimer's disease in Down's syndrome, and their evaluation may help identify people in the preclinical stages of Alzheimer's disease.